Arginase and the Aging Cardiovascular System

精氨酸酶与衰老的心血管系统

• 批准号: 7681858
• 负责人: DAN E BERKOWITZ
• 金额: $ 15.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681858
• 关键词: Acute; Age; Aging; Agonist; Antioxidants; Arginine; Attenuated; Blood Vessels; Cardiovascular Physiology; Cardiovascular system; Cell Aging; Cells; Chronic; Coupling; Data; Disease; Endothelial Cells; Enzymes; Equilibrium; Functional disorder; Measures; Mediating; Nitric Oxide Synthase; Nutritional; Organism; Oxidative Stress; Phenotype; Play; Production; Protein Isoforms; Proteins; Rattus; Reactive Oxygen Species; Regulation; Relative (related person); Relaxation; Role; Signal Pathway; Signal Transduction; Source; Supplementation; Therapeutic; Tissues; Up-Regulation; Vasodilation; Vasodilation disorder; Vasodilator Agents; Ventricular; age related; arginase; cardiovascular risk factor; cell age; functional restoration; human NOS3 protein; improved; inhibitor/antagonist; insight; normal aging; novel; omega-N-Methylarginine; research study; senescence; shear stress; urea cycle; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): Abnormal endothelial NO vasodilator mechanisms contribute to increased cardiovascular risk in the aging cardiovascular system. L-arginine, the NO synthase substrate, improves endothelial dependent vasodilatation by unknown mechanism(s), since intracellular concentrations of L-arginine far exceed the Kd for nitric oxide synthase (NOS). The observation that L-arginine administration increases NO synthesis and enhances endothelial function even in the setting of apparently adequate L-arginine levels in the cell has come to be called the "L-arginine paradox". Arginase, an enzyme of the urea cycle also uses L-arginine as a substrate and is present in cardiovascular tissue. Our preliminary data demonstrate that the L-arginine metabolizing enzyme, arginase, reciprocally regulates vascular endothelial NOS activity, and directly influences vascular relaxation in rats. Furthermore, arginase activity and expression are increased in agingrat vessels, and arginase inhibition attenuates the increased reactive oxygen species (ROS) produced in old rat vascular tissue. We hypothesize that: 1) endothelial arginase limits endothelial NO production and thus, endothelial-dependent vasodilatation, by competing for intracellular L-arginine; 2) vascular endothelial dysfunction of aging is associated with increased expression of endothelial arginase, and inhibition of arginase restores NO-dependent signaling and endothelial function to that of the young phenotype; 3) relative substrate (L-arginine) deficiency enhances ROS production further compromising endothelial function by altering the balance between NO and 02-; and 4) chronic arginase inhibition will restore Larginine reponsiveness, enhance NO signaling, and decrease ROS production thereby restoring altered integrated cardiovascular parameters (increased vascular and ventricular stiffness and altered ventriculararterial coupling) to that of the young phenotype. We will study the regulatory role of arginase in normal endothelial function and NO signaling, as well as its role in the pathophysiology of endothelial dysfunction associated with aging. These experiments will offer novel insights into regulation of the NO signaling pathway, and the balance between NO and 02- in endothelial function, with important therapeutic implications for a wide variety of disorders characterized by endothelial dysfunction.

描述（由申请人提供）：内皮NO血管扩张剂机制异常导致心血管系统老化风险增加。由于细胞内l -精氨酸浓度远远超过一氧化氮合酶（NOS）的Kd， NO合酶底物l -精氨酸通过未知机制改善内皮依赖性血管舒张。观察到，即使在细胞中l -精氨酸水平明显充足的情况下，给予l -精氨酸也能增加NO合成并增强内皮功能，这被称为“l -精氨酸悖论”。精氨酸酶，一种尿素循环的酶也使用l -精氨酸作为底物，存在于心血管组织中。我们的初步数据表明，l -精氨酸代谢酶，精氨酸酶，相互调节血管内皮NOS活性，并直接影响血管舒张。此外，精氨酸酶的活性和表达在阴道血管中增加，精氨酸酶的抑制减弱了老年大鼠血管组织中产生的活性氧（ROS）的增加。我们假设：1)内皮精氨酸酶通过竞争细胞内的l-精氨酸来限制内皮NO的产生，从而限制内皮依赖性血管舒张；2)衰老血管内皮功能障碍与内皮精氨酸酶表达增加有关，抑制精氨酸酶可使no依赖信号和内皮功能恢复到年轻表型；3)相对底物（l -精氨酸）缺乏通过改变NO和02-之间的平衡而增加ROS的产生，进一步损害内皮功能；4)慢性精氨酸酶抑制将恢复精氨酸反应性，增强NO信号，减少ROS的产生，从而将改变的心血管综合参数（血管和心室刚度增加，心室-动脉耦合改变）恢复到年轻表型。我们将研究精氨酸酶在正常内皮功能和NO信号中的调节作用，以及它在内皮功能障碍与衰老相关的病理生理中的作用。这些实验将为NO信号通路的调节以及NO和02-在内皮功能中的平衡提供新的见解，对以内皮功能障碍为特征的各种疾病具有重要的治疗意义。

项目成果

Upregulation of arginase-II contributes to decreased age-related myocardial contractile reserve.

精氨酸酶-II 的上调导致与年龄相关的心肌收缩储备下降。

• DOI: 10.1007/s00421-011-2257-9
• 发表时间: 2012
• 期刊: European journal of applied physiology
• 影响因子: 3
• 作者: Khan,Mehnaz;Steppan,Jochen;Schuleri,KarlH;Schuleri,Karl;Ryoo,Sungwoo;Tuday,Eric;Bugaj,Lukasz;Santhanam,Lakshmi;Berkowitz,Tal;Nyhan,Daniel;Shoukas,ArtinA;Berkowitz,DanE
• 通讯作者: Berkowitz,DanE

Enhanced vasodilatory responses to milrinone in catecholamine-precontracted small pulmonary arteries.

儿茶酚胺预收缩小肺动脉中米力农的血管舒张反应增强。

• DOI: 10.1213/01.ane.0000115781.69209.59
• 发表时间: 2004
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Jhaveri,Rajiv;Kim,Soonyul;White,ARon;Burke,Sean;Berkowitz,DanE;Nyhan,Daniel
• 通讯作者: Nyhan,Daniel

Review article: implications of vascular aging.

• DOI: 10.1213/ane.0b013e3182147e3c
• 发表时间: 2011-05
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Barodka VM;Joshi BL;Berkowitz DE;Hogue CW Jr;Nyhan D
• 通讯作者: Nyhan D

Leptin is essential in maintaining normal vascular compliance independent of body weight.

瘦素对于维持正常的血管顺应性（与体重无关）至关重要。

• DOI: 10.1038/ijo.2009.208
• 发表时间: 2010
• 期刊: International journal of obesity (2005)
• 作者: Sikka,G;Yang,R;Reid,S;Benjo,A;Koitabashi,N;Camara,A;Baraban,E;O'Donnell,CP;Berkowitz,DE;Barouch,LA
• 通讯作者: Barouch,LA

Decreased erythrocyte deformability after transfusion and the effects of erythrocyte storage duration.

• DOI: 10.1213/ane.0b013e31828843e6
• 发表时间: 2013-05
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Frank SM;Abazyan B;Ono M;Hogue CW;Cohen DB;Berkowitz DE;Ness PM;Barodka VM
• 通讯作者: Barodka VM